Reduction of the Estrogenic Side Effects of the Mammary Tumor‐Inhibiting Drug [1,2‐Bis(2,6‐dichloro‐4‐hydroxyphenyl)‐ethylenediamine]dichloroplatinum(II) by Variation of Ring Substituents

Abstract

[1,2-Bis(4-methoxy/4-hydroxyphenyl)ethylenediamine]dichloroplatinum-(II) complexes with Cl-, CH3-, or OCH3-substituents in the ortho-positions of the aromatic rings (meso-1-PtCl2, D,L-1-PtCl2, meso-2-PtCl2, D,L-2-PtCl2, meso-3-PtCl2, meso-4-PtCl2, meso-5-PtCl2) were tested on the MDA-MB 231 breast cancer cell line, the lymphocytic leukemia P388, and the estrogen receptor-positive and -negative MXT mammary carcinoma of the mouse (MXT,ER(+)-MC, MXT,ER(-)-MC). The comparison of the effects of methoxy-substituted complexes (meso-1-PtCl2, D,L-1-PtCl2, meso-3-PtCl2) with those of the respective hydroxy-substituted ones (meso-2-PtCl2, D,L-2-PtCl2, meso-4-PtCl2) shows that a reduction of estrogenic effects as well as a total loss of the mammary tumor-inhibiting activity takes place on methylation of the 4-OH group. The exchange of the 2,6-standing chlorine atoms by methyl groups in meso-2-PtCl2 led to the non-estrogenic, but on the MXT,ER(+)-MC highly effective derivative meso-4-PtCl2 which proved to be also cytotoxic on ER(-)-tumors such as MXT,ER(-)-MC, and the P388 leukemia.

Tumour-inhibiting platinum complexes—state of the art and future perspectives

“…Several of these complexes strongly inhibit growth of hormone-dependent rat mammary tumours. (Anti)oestrogenic effects seem to prevail over a DNA damaging mode of action in those compounds which exhibit selectivity for hormone-sensitive tumours (Karl et al 1988;Schlemmer et al 1999;Gust et al 2000), whereas a lack of endocrine effects is mostly associated with either a loss of selectivity or even a total loss of activity (Gust and Schönenberger 1993;Gust et al 1995). Complexes containing 2-phenylindole ligands show a higher affinity for the oestrogen receptor and a marked selectivity for hormone-dependent tumours.…”